Abstract 1366: Cardiomyocyte-Specific Overexpression of Nox4 Attenuates Cardiac Remodeling in Response to Chronic Pressure Overload
Reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular hypertrophy (LVH). Cardiomyocytes express both Nox2 and Nox4 isoforms of NADPH oxidase, which are major sources of cardiovascular ROS. Previous studies showed that Nox2 plays an important role in angiotensin II-induced cardiac hypertrophy and contractile dysfunction but is not essential for the development of pressure-overload LVH per se. The aim of this project was to investigate the role of Nox4 in pressure-overload LVH in vivo. We generated transgenic mice (TG) with cardiomyocyte-specific overexpression of Nox4, expressing the mouse full-length Nox4 cDNA under control of the α-MHC promoter. TG were backcrossed onto a C57Bl6/J background and wild-type littermates (WT) used as controls. Nox4 TG mice were grossly similar to WT in terms of body weight, growth, activity, fertility and basal cardiac function. TG displayed heart-specific expression of the Nox4 transgene, had 18-fold higher Nox4 protein expression, over 60% higher heart NADPH oxidase activity and increased hydrogen peroxide production (all P<0.05). Compared with WT, p22phox protein expression was increased by 2.4-fold (P<0.05), which may account for the fact that the relative increase in ROS production was less than that in Nox4 protein levels. There was no change in protein expression level of Nox2 or eNOS. Animals underwent abdominal aortic banding or sham banding for up to 9 weeks. Compared with WT/band, the TG/bands displayed less hypertrophy - heart/body weight ratio increased 55% less than WT/band and myocyte cross-sectional area increased 45% less (both P<0.05). TG/band developed significantly less interstitial cardiac fibrosis and had significantly better preserved contractile function both by echocardiography and in vivo pressure-volume analysis. Among possible pathways that may be implicated in these protective effects, we found that TG had enhanced phosphorylation of AKT and GSK-3β but not ERK1/2. In contrast to Nox2, which contributes to contractile dysfunction and hypertrophy, cardiomyocyte Nox4 was found to exert protective effects against the adverse consequences of exposure to chronic pressure overload.